Uromodulin, an emerging novel pathway for blood pressure regulation and hypertension.

Tamm–Horsfall protein was discovered in 1950 by Igor Tamm and Frank Horsfall, using a salt precipitation procedure to isolate a potent inhibitor of viral hemagglutination from urine. Muchmore and Decker, in 1985, isolated a glycoprotein (calling it uromodulin) with in vitro immunosuppressive properties from urine of pregnant women. In 1987, Pennica et al confirmed by cDNA analysis that uromodulin and Tamm–Horsfall protein were identical proteins. Since the initial discovery and without any clear understanding of the function of uromodulin, it was only in 2002 when Hart et al identified causative uromodulin mutations in a subset of families having familial juvenile hyperuricemic nephropathy and medullary cystic kidney disease type 2 that interest in uromodulin biology and function was revived. Interest in uromodulin was further revitalized by genome-wide association studies (GWASs) in 2009/2010 showing an association between common single-nucleotide polymorphisms in the upstream region of the UMOD gene with renal function and hypertension. In 2013, 2 independent groups undertaking post-GWAS functional dissection of the UMOD loci provided molecular insights into a new pathway for hypertension and sodium homeostasis involving uromodulin and opening an exciting line of investigation that could enhance our understanding of renal tubule physiology, sodium homeostasis, blood pressure (BP) regulation, and potentially lead to novel therapies for hypertension. Uromodulin is a protein exclusively expressed by epithelial cells of the thick ascending limb of Henle’s loop (TAL; Figure 1). The 640 amino-acid precursor is cotranslationally translocated into the endoplasmic reticulum (ER), extensively glycosylated, glypiated, and glycosylphosphatidylinositol anchored to the apical tubular cell membrane. From here it is released by a specific, but as yet unidentified, serine protease(s). The released protein is excreted in the urine at a rate of 20 to 100 mg/d and represents the most abundant urinary protein in the healthy individual and is the main constituent of hyaline urinary casts. UMOD Gene and Biology UMOD is located on the reverse strand of chromosome 16 (16p12.3) at position 20 344 374 to 20 367 623 bp (GRCh37/ hg19 assembly). The gene is composed of 11 exons with several alternatively spliced transcripts. The transcription specificity of UMOD to the kidney is determined by its cisacting promoter sequence—in humans, the 5.6 kbp of human genomic sequence, consisting of 3.7 kbp promoter, exon 1, intron 1, and the untranslated part of exon 2. Zhu et al reported the first 589 bp of the UMOD promoter as highly conserved across species (human, rat, mouse, and cow) and that the 3 Kb promoter region drives TAL-specific expression of UMOD. From cDNA sequence, the uromodulin precursor is composed of 640 amino-acid residues, and motifs include signal sequence (residues 1–24) directing its entry in the secretory pathway; 1 epidermal growth factor–like and 2 calcium-binding epidermal growth factor–like domains (residues 31–64, 65–107, and 108–149) which have roles in adhesion, coagulation, and receptor–ligand interaction; 1 central domain of unknown function (named D8C containing eight conserved cysteines); 1 zona pellucida domain (residues 334–585) essential for protein polymerization; a glycosylphosphatidylinositol attachment site (residue 614); and 8 potential N-glycosylation sites. The molecular weight of uromodulin (105 kDa) is significantly contributed (30%) by N-glycosylation, and there are 48 cysteine residues involved in disulfide bond formation. The uromodulin signal peptide is cleaved in the ER, the protein is glycosylated on 7 of its 8 potential N-glycosylation sites, disulphide bridges are formed, and glypiation on its C terminus occurs. The Golgi apparatus further modifies the N-glycan moieties. The mature glycan moieties and the glycosylphosphatidylinositol modifications route the protein to the apical membrane of TAL epithelial cells, where uromodulin is finally glycosylphosphatidylinositol anchored facing the tubular lumen. ER processing is the rate-limiting step in uromodulin maturation (Figure 1). From the luminal side of the membrane, the protein is actively released by proteolytic cleavage at residue F587 (Figure 1). This implies that urinary uromodulin is composed of 563 amino acids